The goal of this project is specifically aligned with the NIH request for applications to define the most effective use of existing TB therapies and to provide preliminary data to support the NIAID aim of making therapy more potent and easier to tolerate and developing shorter treatment regimens. This project also contributes to the broader aim of the WHO Stop TB Partnership to realize the goal of eliminating TB as a public health problem. The specific aim of this project is to plan a clinical trial that will administer aerosolized isoniazid (INH), rifampin (RIF) and streptomycin (SM) to healthy volunteers and measure the concentration of each drug in the blood and lungs at set time intervals. Pharmacokinetic and pharmacodynamic (PKPD) parameters will be analyzed using compartmental and population methods. PKPD analysis will provide important information about using adjunctive aerosol therapy to overcome resistance, decrease systemic toxicity and increase the rate of sputum conversion to decrease contagiousness. Furthermore, development of aerosol treatment using first line drugs may provide treatment options in developing parts of the world with the highest TB burden, where second line and new drugs are too costly. However, treatment strategies and outcomes will have to be determined in future controlled clinical trials. Methods will include administering aerosolized INH, RIF or SM to human subjects and collecting samples at set intervals after administration. Samples from the blood and lungs will be obtained by venipuncture and bronchoalveolar lavage (BAL). BAL is performed by an expert pulmonologist who inserts a long, thin, flexible scope into the lungs through the mouth and throat. Saline is put into the lungs through the instrument and immediately suctioned out and collected. The concentration of each drug in the blood and lungs will be measured by a sensitive and specific assay (liquid chromatography (LC) / mass spectroscopy (MS)). Those measurements are compared to the concentrations of drug necessary to inhibit growth of the bacteria that causes TB. We will analyze how drug concentrations change over time after aerosolized administration and compare this data to the plasma and intrapulmonary PKPD of the same drugs by standard administration methods. PKPD analysis will be done using both compartmental and population methods. PUBLIC HEALTH RELEVANCE: Aerosol treatment, adjunct to standard therapy, may improve treatment and reduce the spread of drug-sensitive and drug-resistant tuberculosis. We hypothesize that aerosol delivery will a) achieve pulmonary concentrations high enough to overcome resistance b) achieve plasma concentrations low enough to minimize toxicity and c) lead to more rapid sputum sterilization. This study may contribute to controlling the spread of tuberculosis because more rapid sputum sterilization would reduce the duration of contagiousness.